epigenetic mechanisms: mediating between experience & mental & physical health
TRANSCRIPT
M M M MMM
Epigenetic mechanisms mediating between experience and mental and physical health
Moshe Szyf
Department of Pharmacology and Therapeutics
McGill University, Montreal Canada
The Science of HopeFoundation for healthy generations Seattle, Washington,
April 19 2016
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DNA METHYLATION REACTIONS
Epigenetic marks (i.e. DNA methylation) at critical positions silence genes;
same gene could be either active or silent based on the state of methylation
X
Tet H2OH
X
DNA methylation inhibits RNA Pol2 complex binding
.TBP
TBP
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me
thy
las
e
de
me
thy
las
e
active
inactive
The gene is an equilibrium between activity and lack of activity that is defined by
epigenetic marks. Epigenetic marks program how genes work in different organs
in our body;
This equilibrium could be reset by environmental signals
nutrients
toxinssocial
behavioral pathological
physiological
DNA METHYLATION a mechanism of adaptation of the genome
in response to changing environments without changing the
sequence of DNA
•Evolutionary time scale
•Trans-generational time scale
•Life long time scale
•Life cycle stations time scale
•Seasonal time scale
•Physiological proximal time scale
Bioenvironment Physical environment Social environment
phenotype
Bioenvironment Physical environment Social environment
Health challenges
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System wide
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Signaling pathways
Adaptive response of the genome in early life
LOW LG HIGH LG
STRESS RESPONSE STRESS RESPONSE
A bar in Madrid, licking rats and the birth of the field of “behavioral epigenetics”
Pups
Adults
Biological mother Adoptive mother
Low LG
Low LGHigh LG
High LG
Behavioral programming by the mother is epigenetic not genetic;
The fostering mother and not the biological mothers transfers the phenotype
Cross-fostering /adoption
experiment
PKA
Behavioral gene programming is stable but nevertheless reversible
5-HT
cAMP
NGFI-A
HAT
DemethylaseMBD2?
DNMT
TSA
Methionine
The signature of maternal care in non-
human primates
Mother Surrogate
Stephen Suomi
Genome wide view of the differential methylation between maternal and nursery reared rhesus monkeys in T cells and
prefrontal cortex
PROMOTER METHYLATION RESPONSE TO early life stress Maternal deprivation in
T CELLS AND PFC
Rearing = mother
/ nursery
high
low
me
thylatio
nPFC T cells
Quebec ice storm 1998
Storm32 score
ThreatLoss
Scope Change
DNA methylation signatures of randomized objective stress during pregnancy in
human adolescent T cells Quebec ice storm of 1998
storm32
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30
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6 9
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6
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7
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36
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100 C
pG
sites
storm32 heatmap
storm32
1206
1206
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449
30
879
1368
51
135
287
948
948
1210
384
39
1191 8
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826 9
827
1316
1315
115
1365
405
1248
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56
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105
1060
1036
363
promoters
storm32 heatmap
stress%low%medium%high%
high%
low%
methyla1
on%
samples%
CpG%sites%
The$DNA$methylation$signature$of$maternal$stress$in$chord$blood$T$cells:
Correlation between objective randomized stress during pregnancy and CG methylation
in the SCG5 gene in T cells of 15 year old
Objective stress during ice storm 1998
Meth
yla
tio
n
Ice storm data suggested enrichment of type 1 diabetes pathway
Type 1 diabetes signaling pathway enriched with differentially methylated genes that correlate with objective stress
DNA methylation mediates the long term impact of
adult experience, for example, chronic pain, addiction;
Diagnostic and therapeutic implications
Transcription
factorX
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X
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factor
XAcAc Ac
Transcription
Machinery
Transcription
machineryDNMT
Demethylases
Protein A Protein AX
Phenotype A Phenotype B
RG108
SAM
Behavioral intervention
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factorX
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X
Transcription
factor
XAcAc Ac
Transcription
Machinery
Transcription
machineryDNMT
Demethylases
Protein A Protein AX
Phenotype A Phenotype B
Figure 1
RG108
SAM
Behavioral intervention
Incubation model of cocaine craving
Copyright 2013, Western Washington University,
Behavioral Neuroscience Program/Grimm lab
RG108, SAM or aCSF
injections
Days
cocaine (Coc.) or saline (Sal.)
self-administration (SA)
withdrawal
10 days0 1 Day 30
Day 1 groups:- Sal. SA: Sal.- Coc. SA no cue: 1W- Coc. SA cue: 1C
Day 30 groups:- Coc. SA no cue: 30W- Coc. SA cue: 30C+- Coc. SA cue-aCSF: aCSF- Coc. SA cue-RG108 cue: RG108- Coc. SA cue-SAM: SAM- Coc. SA cue-PPT- Coc. SA cue-roscovitine
RG108 or aCSFinjections
Days
10 days
0-2cocaine
self-administration
a
b
FIGURE 1
Day 60
withdrawal
Day 60 groups:
- Coc. SA cue-aCSF: aCSF-60
- Coc. SA cue-RG108 cue: RG108-60
- Coc. SA cue-SAM: SAM-60
EPM, locomotion, memory tests
Withdrawal intensifies craving
Yadid
DNA methylation changes following cocaine
administration, cues and withdrawal
Epigenetic modulation reprograms craving behavior only at
the end of a long withdrawal period when paired with a cue
Combined behavioral and epigenetic therapy
b
FIGURE 5
0
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Training Test0
20
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aCSF
RG108
Dis
tan
ce (cm
)
Tim
e in
op
en
arm
(sec)
caCSF
RG108
aCSF
RG108
Exp
lora
tio
n (%
)
d
0
20
40
60
80
** *
0
30
60
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120 ****
a
Lever
pre
sses
D30 D60
D30 D60
aCSF
SAM
Lever
pre
sses
f
aCSF
RG108
0
30
60
90
120
e
Lever
pre
sses
Before injection
After injection
**
**
b
FIGURE 5
0
500
1000
1500
0
50
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150
200
250
Training Test0
20
40
60
80
aCSF
RG108
Dis
tan
ce (cm
)
Tim
e in
op
en
arm
(sec)
caCSF
RG108
aCSF
RG108
Exp
lora
tio
n (%
)
d
0
20
40
60
80
** *
0
30
60
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120 ****
a
Lever
pre
sses
D30 D60
D30 D60
aCSF
SAM
Lever
pre
sses
f
aCSF
RG108
0
30
60
90
120
e
Lever
pre
sses
Before injection
After injection
**
**
b
FIGURE 5
0
500
1000
1500
0
50
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150
200
250
Training Test0
20
40
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80
aCSF
RG108
Dis
tan
ce (cm
)
Tim
e in
op
en
arm
(sec)
caCSF
RG108
aCSF
RG108
Exp
lora
tio
n (%
)d
0
20
40
60
80
** *
0
30
60
90
120 ****
a
Lever
pre
sses
D30 D60
D30 D60
aCSF
SAM
Lever
pre
sses
f
aCSF
RG108
0
30
60
90
120
e
Lever
pre
sses
Before injection
After injection
**
**
RG108 DNA methyl transferase inhibitor
After long withdrawal immediately after training
SAM DNA methylation stimulator
ESR1 and CDK5 are modulated by DNA methylation inhibitors in the cocaine craving model; ESR1 agonist propyl pyrazole triol (PPT) and CDK5 antagonist (roscovitine) reverse cocaine craving
FIGURE 7
Cdk5chr4
0
-0.78
500 b
Esr1
27 kb
chr1
0
-0.39
Esr1
mRN
A
0.0
0.4
0.8
1.2 *aCSF roscovitine
CDK5 inhibitor
0
400
800
1200
0
30
60
90
120
150**
Leve
r pre
sses
Loco
mot
ion
0.0
0.4
0.8
1.2
1.6
aCSF PPT
ESR1 agonist
0
400
800
1200
0
20
40
60
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100
Leve
r pre
sses
****
Loco
mot
ion
Cdk5
mRN
A
aCSF RG108
DNMT inhibitor
aCSF RG108
DNMT inhibitor
DNA
meth
ylatio
n DN
A m
ethyla
tion
a
b
FIGURE 7
Cdk5chr4
0
-0.78
500 b
Esr1
27 kb
chr1
0
-0.39
Esr1
mR
NA
0.0
0.4
0.8
1.2 *aCSF roscovitine
CDK5 inhibitor
0
400
800
1200
0
30
60
90
120
150**
Leve
r pre
sses
Loco
mot
ion
0.0
0.4
0.8
1.2
1.6
aCSF PPT
ESR1 agonist
0
400
800
1200
0
20
40
60
80
100
Leve
r pre
sses
****
Loco
mot
ion
Cdk
5 m
RN
A
aCSF RG108
DNMT inhibitor
aCSF RG108
DNMT inhibitor
DN
A m
ethy
latio
n D
NA
met
hyla
tion
a
b
What are the implications of a life-long dynamic
epigenome?
chemical social
Signaling pathways
phenotype
biosphere
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AcknowledgementsAnne McKiney
Tony Huang
Ziv Machnes
Gustavo Turecki
Michael Meaney
Ian Weaver
Patrick McGowan
Michael Hallett,
Matt Suderman
Stephen Suomi, Allyson Bennett, Peter Pierre
Nadine Provencal
Renaud Massart
Laura Stone
Lei Cao
Suzan King
Gal Yadid (BIU)
Renaud Massart
Royi Barnea (BIU)
Yahav Dikshtein (BIU)
Oren Meir (BIU)
Peter Gass
Michaela Schmidt
THIS RESEARCH IS SUPPORTED BYGRANTS FROM CIHR MRC, the Sackler program in
epigenetics and psychobiology